Efficient lipid delivery to human tear film using a salt-sensitive emulsion system

ABSTRACT

Provided herein are low salt ophthalmic pharmaceutical composition and methods of use thereof, for example, in the treatment of dry eye syndrome.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/078,377, filed Mar. 23, 2016, which is a continuation-in-part of U.S.patent application Ser. No. 13/708,771 filed Dec. 7, 2012, now U.S. Pat.No. 9,314,528, issued Apr. 19, 2016, which in turn claims priority toU.S. Provisional Application Ser. Nos. 61/568,089, filed Dec. 7, 2011and 61/625,401 filed Apr. 17, 2012, the disclosures of which are herebyincorporated in their entireties herein by reference. U.S. patentapplication Ser. No. 15/078,377 is also a continuation-in-part of U.S.patent application Ser. No. 13/708,783, filed Dec. 7, 2012, nowabandoned, which in turn claims priority to U.S. Provisional ApplicationSer. Nos. 61/568,089, filed Dec. 7, 2011 and 61/625,401 filed Apr. 17,2012, the disclosures of which are hereby incorporated in theirentireties herein by reference.

BACKGROUND OF THE INVENTION

The present application relates to compositions and methods tosupplement and enhance the native tear film of the eye, e.g., the nativelipid layer of the tear film. The compositions and methods disclosedherein provide inter alia relief of hyperosmotic stress and otherconditions associated with dry eye syndrome.

Delivering therapeutic agents, e.g., therapeutic lipids, to supplementand enhance the native tear film is a recognized strategy in treatingsymptoms of dry eye syndrome. Without wishing to be bound by any theory,it is believed that this strategy is especially advantageous underconditions of low humidity or when other factors increase tear filmevaporation. In dry eye syndrome, loss of water in the tear film canlead to increased salt content at the ocular surface, which in turn canlead to hyperosmotic stress to the cells of the ocular surface. It isfurther believed that the native lipid layer of the tear film functionsinter alia to reduce evaporation from the underlying aqueous tear filmlayer. Accordingly, in cases where the native lipid layer is reduced,e.g., in disorders or conditions described herein or known in the art,it is believed that supplementation and enhancement of the lipid layerof the tear film is beneficial.

The lipid layer of the native tear film is quite thin (i.e., 0.1-0.2micron). Moreover, the total volume of lipid in the tear film is but asmall fraction of the total tear film volume. Thus, previous methods ofsupplementation and enhancement of the structure and function of thelipid layer of the tear film by topical application of alipid-containing pharmaceutical composition require merely a smalltherapeutically effective volume of lipid to be delivered. In suchmethods, however, excess lipid provided during instillation can displaceand disrupt the aqueous component of the tear film. Because the lipiddelivered by such methods needs to become established as part of thenative lipid layer, at the air interface over the aqueous tear, methodswhich reduce the aqueous layer of the tear film can afford reducedeffectiveness. Moreover, any topical drop delivery method ofsupplementation and enhancement of the lipid layer of the tear filmrequires rapid delivery during the brief contact time of the topical eyedrop with the ocular surface.

Thus, previous methods of supplementing and enhancing the lipid layer ofthe tear film have been addressed by a variety of approaches, includingusing a substantial amount of lipid (e.g., 1-5%) and/or building anemulsion system that readily separates. However, such methods suffermultiple disadvantages, including a requirement for shaking of thecomposition prior to instillation, reduced clarity of the compositionupon instillation, variability of the total volume of lipid delivered tothe eye, and problems with tolerability vis-a-vis aqueous eye drops.

Typical symptoms of keratoconjunctivitis or dry eye include feelings ofdryness, burning, and a sandy-gritty eye sensation that can worsenduring the day. Symptoms may also be described as itchy, scratchy,stingy or tired eyes. Other symptoms include pain, redness, a pullingsensation, and pressure behind the eye. The damage to the eye surfaceresulting from dry eye increases discomfort and sensitivity to brightlightand both eyes usually are affected.

Because blinking coats the eye with tears, symptoms are worsened byactivities in which the rate of blinking is reduced due to prolonged useof the eyes. These activities include prolonged reading, computer usage,driving or watching television. Symptoms increase in windy, dusty orsmoky areas, in dry environments, high altitudes including airplanes, ondays with low humidity, and in areas where an air conditioner, fan, orheater, is being used. Symptoms are less severe during cool, rainy, orfoggy weather, and in humid places. Most people who have dry eyesexperience mild irritation with no long-term effects. However, if thecondition is left untreated or becomes severe, it can producecomplications that can cause eye damage, resulting in impaired vision orpossibly in the loss of vision.

Having dry eyes for a prolonged period of time can lead to tinyabrasions on the surface of the eyes. In advanced cases, the epitheliumundergoes pathologic changes, namely squamous metaplasia and loss ofgoblet cells sometimes due to activation of T cells acting against thosecells. Some severe cases result in thickening of the corneal surface,corneal erosion, punctate keratopathy, epithelial defects, cornealulceration, corneal neovascularization, corneal scarring, cornealthinning, and even corneal perforation. An abnormality of any one of thethree layers of tears which produces an unstable tear film, may resultin symptoms of keratitis sicca.

Keratoconjunctivitis sicca is usually due to inadequate tear production.The aqueous tear layer is affected, resulting in aqueous tear deficiencyor lacrimal hyposecretion. The lacrimal gland does not producesufficient tears to keep the entire conjunctiva and cornea covered by acomplete layer. This usually occurs in people who are otherwise healthy.Increased age is associated with decreased tearing. This is the mostcommon type found in postmenopausal women. Causes include idiopathic,congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensorydenervation. In rare cases, it may be a symptom of collagen vasculardiseases, including rheumatoid arthritis, Wegener's granulomatosis, andsystemic lupus erythematosus. Sjögren's syndrome and autoimmune diseasesassociated with Sjögren's syndrome are also conditions associated withaqueous tear deficiency. Drugs such as isotretinoin, sedatives,diuretics, tricyclic antidepressants, antihypertensives, oralcontraceptives, antihistamines, nasal decongestants, beta-blockers,phenothiazines, atropine, and pain-relieving opiates such as morphinecan cause or worsen this condition. Infiltration of the lacrimal glandsby sarcoidosis or tumors, or postradiation fibrosis of the lacrimalglands can also cause this condition.

Keratoconjunctivitis sicca can also be caused by abnormal tearcomposition resulting in rapid evaporation or premature destruction ofthe tears. When caused by rapid evaporation, it is termed evaporativedry eyes. In this condition, although the tear gland produces asufficient amount of tears, the rate of evaporation of the tears is toorapid. There is a loss of water from the tears that results in tearsthat are too “salty” or hypertonic. As a result, the entire conjunctivaand cornea cannot be kept covered with a complete layer of tears duringcertain activities or in certain environments.

Aging is one of the most common causes of dry eyes. This is due to thefact that tear production decreases with age. It may be caused bythermal or chemical burns, or by adenoviruses. Diabetics are also atincreased risk for dry eye.

An eye injury or other problem with the eyes or eyelids, such as bulgingeyes or a drooping eyelid, can cause keratoconjunctivitis sicca.Disorders of the eyelid can impair the complex blinking motion requiredto spread tears.

About half of all people who wear contact lenses have dry eyes. This isbecause soft contact lenses, which float on the tear film that coversthe cornea, absorb the tears in the eyes.

Dry eye also occurs or gets worse after refractive surgeries, in whichthe corneal nerves are cut during the creation of a corneal flap,because the corneal nerves stimulate tear secretion. Dry eyes caused bythese procedures usually disappear after several months.

Abnormalities of the lipid tear layer caused by blepharitis and rosaceaand abnormalities of the mucin tear layer caused by vitamin Adeficiency, trachoma, diphtheric keratoconjunctivitis mucocutaneousdisorders and certain topical medications may cause dry eye orkeratoconjunctivitis sicca.

Dry eyes can usually be diagnosed by the symptoms alone. Tests candetermine both the quantity and the quality of the tears. A slit lampexamination can be performed to diagnose dry eyes and to document anydamage to the eye. A Schirmer's test can measure the amount of moisturebathing the eye. This test is useful for determining the severity of thecondition.

A variety of approaches can be taken to treatment, such as: avoidance ofexacerbating factors, tear stimulation and supplementation, increasingtear retention, and eyelid cleansing and treatment of eye inflammation.For mild and moderate cases, supplemental lubrication is the mostimportant part of treatment. Application of artificial tears every fewhours can provide temporary relief.

Lubricating tear ointments can be used during the day, but theygenerally are used at bedtime due to poor vision after application. Theycontain white petrolatum, mineral oil, and similar lubricants. Theyserve as a lubricant and an emollient. Depending on the severity of thecondition, ointments may be applied from every hour to just at bedtime.Ointments should not be used with contact lenses. Inflammation occurringin response to tears film hypertonicity can be suppressed by mildtopical steroids or with topical immunosuppressants such ascyclosporine.

The present invention provides, inter alia, compositions and methodsdirected to an alternate means of lipid release by the use of asalt-sensitive emulsion system in an ophthalmic pharmaceuticalcomposition which is largely free of salt. Specifically, the presentcompositions employ a surfactant and a salt-sensitive viscositymodulating polymer to hold a therapeutic lipid (e.g., castor oil) in astable sub-micron emulsion. When instilled in the eye, the compositionmixes with the native tear film, the natural salt content of which issufficient to cause a rapid decrease in viscosity due to changes in thesalt-sensitive viscosity modulating polymer. Upon loss of viscosity,therapeutic lipid is released from the sub-micron emulsion at the eye,thereby providing supplementation and enhancement of the native lipidlayer of the tear film.

SUMMARY OF THE INVENTION

In a first aspect, there is provided a low salt ophthalmicpharmaceutical composition which includes a sub-micron emulsion, apolymer lubricant, and a salt-sensitive viscosity modulating polymer,wherein the sub-micron emulsion includes a surfactant and a therapeuticlipid.

In another aspect, there is provided a low salt ophthalmicpharmaceutical composition including: castor oil at a concentration ofabout 0.25% (w/w); polysorbate 80 at a concentration of about 0.5%(w/w); acrylate/C₁₀-C₃₀ acrylate crosspolymer at a concentration ofabout 0.1% (w/w), wherein said acrylate/C₁₀-C₃₀ acrylate crosspolymerhas a standard emulsion viscosity between 1,700 and 4,500 cPs;carboxymethylcellulose sodium at a concentration of about 0.5% (w/w);glycerin at a concentration of about 1.0% (w/w); a stabilized oxychlorocomplex preservative at a concentration of about 0.01% (w/w); boric acidat a concentration of about 0.6% (w/w); erythritol at a concentration ofabout 0.25% (w/w); levocarnitine at a concentration of about 0.25%(w/w); NaOH; and water.

In another aspect, there is provided a method for treating dry eyesyndrome. The method includes administering to a subject in need oftreatment of dry eye syndrome a low salt ophthalmic pharmaceuticalcomposition as described herein, thereby treating the dry eye syndrome.

TABLE I [1] POLYSORBATE 80 0.5 % w/w Active Grade: NF ph Eur [2]CARBOXYMETHYLCELLULOSE 0.5 % w/w Active SODIUM (LOW VISCOSITY 7LFPH)Grade: Ph Eur USP [3] GLYCERIN 1.0 % w/w Active Grade: Ph Eur USP [4]PURITE 0.01 % w/w Preservative Grade: BORIC ACID 0.6 % w/w Buffer Grade:NF Ph Eur [5] PEMULEN TR-2 0.1 % w/w Stabilizer Grade: NF [6] CASTOR OIL0.25 % w/w Excipient Grade: Eur Ph USP ERYTHRITOL 0.25 % w/w ExcipientGrade: NF Ph Eur LEVOCARNITINE 0.25 % w/w Excipient Grade: Ph Eur USP[7] SODIUM HYDROXIDE 7.3 pH pH Adjust Grade: NF Ph Eur [8] WATER FORINJECTION/ 100 % w/w QS Adjust PURIFIED WATER Grade: USP [1] PM# 12783.Super Refined Polysorbate 80 from CRODA. Primary emulsifer anddemulcent. [2] Demulcent [3] Demulcent and tonicity agent [4] StabilizedOxychloro Complex (Purite). Add by assay value. [5] Pemulen TR-2NF(Carbomer Copolymer Type A, Tested to Ph Eur). Secondary emulsifer. [6]Lipophilic vehicle [7] pH target 7.3 [8] Hydrophilic vehicle

The Table I formulation includes the concentrations of actives and/orexcipients as disclosed above which can be in concentrations which varyfrom what is stated above. The variation may be such that the amountsare “about” what is stated above so long as that amount would be foundbioequivalent by a regulatory agency such as the FDA or the EMEA.

The formulation may be preserved or non-preserved (not containingPurite®), such as a unit dose version. This version would be the same asthat in Table 1 except it would contain no Purite®.

Some embodiments of the invention are included in the followingparagraphs:

-   1) A composition useful as an artificial tear, which is a salt free    emulsion comprising castor oil and specifically excludes olive oil    and contains at least one active agent selected from the group    consisting of polysorbate, carboxymethylcellulose and glycerine.-   2) The composition of paragraph 1 wherein said mixture comprises    from about 0.1%-0.5% w/w, castor oil.-   3) The composition of paragraphs 1-2 wherein castor oil is the only    oil in the emulsion.-   4) The composition of paragraphs 1-3 wherein the castor oil is    emulsified in an aqueous phase.-   5) The composition of paragraph 4 wherein the castor oil is present    in about 0.25% w/w.-   6) The composition of paragraphs 4-5 further including a primary and    a secondary emulsifier.-   7) The composition of paragraphs 1-6 wherein the composition    contains a preservative.-   8) The composition of paragraph 7 wherein the preservative is    selected from the group consisting of PURITE and benzalkonium    chloride.-   11. The composition of paragraph 8 wherein the preservative is    PURITE is present in a concentration of about 0.01% w/v.-   12. An emulsion for use in treating dry eye wherein the emulsion is    salt-free and comprises castor oil, polysorbate 80,    carboxymethylcellulose and glycerine.-   13. The composition of paragraph 12 wherein the emulsion also    contains the emulsifier pemulen.-   14. The emulsion of paragraphs 12-13 further comprising erythritol    and levocarnitine.-   15. An emulsion for treating dry eye as shown in Tables I, II or    III.-   16. A method of treating dry eye comprising administration of any    one of the compositions or emulsions of paragraphs 1-15.-   17. A composition for the treatment of dry eye or    keratoconjunctivitis sicca wherein the composition comprises about    0.5% w/w Polysorbate 80, about 0.5% w/w carboxymethylcellulose,    about 1.0% w/w glycerine, about 0.6% w/w boric acid, about 0.1% w/w    pemulen, about 0.25% w/w castor oil, about 0.25% w/w erythritol,    about 0.25% w/w levocarnitine, sodium hydroxide to adjust the pH to    about 7.3 and water.-   18. The composition of paragraph 17 further comprising 0.01%    Purite®.-   19. The composition of paragraph 17 wherein the composition is    applied topically to an eye which is suffering from dry eye.-   20. The composition of paragraph 17 wherein the composition is    applied topically to an eye to alleviate the symptoms of dry eye.-   21. The composition of paragraph 17 wherein the composition is    applied topically to an eye to prevent dry eye syndrome.-   22. A low salt ophthalmic pharmaceutical composition comprising a    sub-micron emulsion, a polymer lubricant, and a salt-sensitive    viscosity modulating polymer, wherein said sub-micron emulsion    comprises a surfactant and a therapeutic lipid.-   23. The low salt ophthalmic pharmaceutical composition of paragraph    22, wherein said composition is clear.-   24. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 21 to 23, wherein said therapeutic lipid is a    fatty acid glyceride.-   25. The low salt ophthalmic pharmaceutical composition according to    paragraph 24, wherein said fatty acid glyceride is a castor oil,    olive oil, peanut oil, corn oil, or sunflower oil.-   26. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 25, wherein said therapeutic lipid is    castor oil.-   27. The low salt ophthalmic pharmaceutical composition according to    paragraph 26, wherein said castor oil is present at a concentration    between about 0.01% (w/w) and about 10% (w/w).-   28. The low salt ophthalmic pharmaceutical composition according to    paragraph 27, wherein said castor oil is present at a concentration    of about 0.25% (w/w).-   29. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 28, wherein said surfactant is a    sorbitan ester.-   30. The low salt ophthalmic pharmaceutical composition according to    paragraph 29, wherein said surfactant is polysorbate 80.-   31. The low salt ophthalmic pharmaceutical composition according to    paragraph 30, wherein said polysorbate 80 is present at a    concentration between about 0.01% (w/w) and about 1.0% (w/w).-   32. The low salt ophthalmic pharmaceutical composition according to    paragraph 31, wherein said polysorbate 80 is present at a    concentration of about 0.5% (w/w).-   33. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 32, wherein said salt-sensitive    viscosity modulating polymer is an acrylate/C10-C30 acrylate    crosspolymer.-   34. The salt-sensitive viscosity modulating polymer according to    paragraph 33 having a standard emulsion viscosity between 1,700 and    4,500 cPs.-   35. The low salt ophthalmic pharmaceutical composition according to    paragraph 34, wherein said salt-sensitive viscosity modulating    polymer is present at a concentration between about 0.01% (w/w) and    about 1.0% (w/w).-   36. The low salt ophthalmic pharmaceutical composition according to    paragraph 35, wherein said salt-sensitive viscosity modulating    polymer is present at a concentration of about 0.1% (w/w).-   37. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 36, wherein said polymer lubricant is a    demulcent.-   38. The low salt ophthalmic pharmaceutical composition according to    paragraph 37, wherein said polymer lubricant is    carboxymethylcellulose sodium present at a concentration between    about 0.01% (w/w) and about 1.0% (w/w).-   39. The low salt ophthalmic pharmaceutical composition according to    paragraph 38, wherein said carboxymethylcellulose sodium is present    at a concentration of about 0.5% (w/w).-   40. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 39, further comprising a compatible    solute.-   41. The low salt ophthalmic pharmaceutical composition according to    paragraph 40, wherein said compatible solute is a polyol or a    zwitterionic amino acid.-   42. The low salt ophthalmic pharmaceutical composition according to    paragraph 41, wherein said compatible solute is erythritol or    levocarnitine.-   43. The low salt ophthalmic pharmaceutical composition according to    paragraph 42, wherein said compatible solute is erythritol present    at a concentration between about 0.01% (w/w) and about 1.0% (w/w).-   44. The low salt ophthalmic pharmaceutical composition according to    paragraph 42, wherein said compatible solute is levocarnitine    present at a concentration between about 0.01% (w/w) and about 1.0%    (w/w).-   45. The low salt ophthalmic pharmaceutical composition according to    paragraph 42, wherein said compatible solute is erythritol at a    concentration of about 0.25% (w/w).-   46. The low salt ophthalmic pharmaceutical composition according to    paragraph 42, wherein said compatible solute is levocarnitine at a    concentration of about 0.25% (w/w).-   47. The low salt ophthalmic pharmaceutical composition according to    paragraph 42 comprising erythritol at a concentration of about 0.25%    (w/w) and levocarnitine at a concentration of about 0.25% (w/w).-   48. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22-47, further comprising a tonicity agent.-   49. The low salt ophthalmic pharmaceutical composition according to    paragraph 48, wherein said tonicity agent is a demulcent.-   50. The low salt ophthalmic pharmaceutical composition according to    paragraph 48, wherein said tonicity agent is glycerin present at a    concentration between about 0.01% (w/w) and about 5.0% (w/w).-   51. The low salt ophthalmic pharmaceutical composition according to    paragraph 50, wherein said glycerin is present at a concentration of    about 1.0% (w/w).-   52. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 21-51, further comprising a preservative.-   53. The low salt ophthalmic pharmaceutical composition according to    paragraph 52, wherein said preservative is a stabilized oxychloro    complex.-   54. The low salt ophthalmic pharmaceutical composition according to    paragraph 53, wherein said preservative is present at a    concentration between about 0.001% (w/w) and about 0.1% (w/w).-   55. The low salt ophthalmic pharmaceutical composition according to    paragraph 53, wherein said preservative is present at a    concentration of about 0.01% (w/w).-   56. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 55, further comprising a buffer.-   57. The low salt ophthalmic pharmaceutical composition according to    paragraph 56, wherein said buffer is boric acid present at a    concentration between about 0.01% (w/w) and about 1.0% (w/w).-   58. The low salt ophthalmic pharmaceutical composition according to    paragraph 57, wherein said boric acid is present at a concentration    of about 0.6% (w/w).-   59. The low salt ophthalmic pharmaceutical composition according to    any one of paragraphs 22 to 38, further comprising a pH adjustment    agent.-   60. The low salt ophthalmic pharmaceutical composition according to    paragraph 59, wherein said pH adjustment agent is NaOH.-   61. The low salt ophthalmic pharmaceutical composition according to    paragraph 59 having pH of about 7.3-   62. The low salt ophthalmic pharmaceutical composition according to    paragraph 60 comprising: castor oil at a concentration between about    0.01% (w/w) and about 10% (w/w); polysorbate 80 at a concentration    between about 0.01% (w/w) and about 1.0% (w/w); acrylate/C10-C30    acrylate crosspolymer at a concentration between about 0.01% (w/w)    and about 1.0% (w/w), wherein said acrylate/C10-C30 acrylate    crosspolymer has a standard emulsion viscosity between 1,700 and    4,500 cPs; carboxymethylcellulose sodium at a concentration between    about 0.01% (w/w) and about 1.0% (w/w); glycerin at a concentration    between about 0.01% (w/w) and about 5.0% (w/w); a stabilized    oxychloro complex preservative at a concentration between about    0.001% (w/w) and about 0.1% (w/w); boric acid at a concentration of    about 0.6% (w/w); erythritol at a concentration of about 0.25%    (w/w); levocarnitine at a concentration of about 0.25% (w/w); NaOH;    and water.-   63. A low salt ophthalmic pharmaceutical composition comprising:    castor oil at a concentration of about 0.25% (w/w); polysorbate 80    at a concentration of about 0.5% (w/w); acrylate/C10-C30 acrylate    crosspolymer at a concentration of about 0.1% (w/w), wherein said    acrylate/C10-C30 acrylate crosspolymer has a standard emulsion    viscosity between 1,700 and 4,500 cPs; carboxymethylcellulose sodium    at a concentration of about 0.5% (w/w); glycerin at a concentration    of about 1.0% (w/w); a stabilized oxychloro complex preservative at    a concentration of about 0.01% (w/w); boric acid at a concentration    of about 0.6% (w/w); erythritol at a concentration of about 0.25%    (w/w); levocarnitine at a concentration of about 0.25% (w/w); NaOH;    and water.-   64. A method for treating dry eye syndrome comprising: administering    to a subject in need of treatment of dry eye syndrome a low salt    ophthalmic pharmaceutical composition according to any one of    paragraphs 22 to 63; thereby treating said dry eye syndrome.-   65. The method of paragraph 64, wherein said therapeutic lipid is    castor oil at a concentration between about 0.01% (w/w) and about    10% (w/w).-   66. The method of any one of paragraphs 64 to 65, wherein said    surfactant is polysorbate 80 at a concentration between about 0.01%    (w/w) and about 1.0% (w/w).-   67. The method of any one of paragraphs 64 to 65, wherein said    salt-sensitive viscosity modulating polymer comprises    acrylate/C10-C30 acrylate crosspolymer present at a concentration    between about 0.01% (w/w) and about 1.0% (w/w), wherein said    salt-sensitive viscosity modulating polymer has a standard emulsion    viscosity between 1,700 and 4,500 cPs.-   68. The method of any one of paragraphs 65 to 67, wherein said    polymer lubricant is carboxymethylcellulose sodium present at a    concentration between about 0.01% (w/w) and about 1.0% (w/w).-   69. The method of any one of paragraphs 64 to 68, further comprising    a compatible solute, wherein said compatible solute is erythritol at    a concentration of about 0.25% (w/w) and levocarnitine at a    concentration of about 0.25% (w/w).-   70. The method of any one of paragraphs 64 to 69, further comprising    a tonicity agent, wherein said tonicity agent is glycerin at a    concentration between about 0.01% (w/w) and about 5.0% (w/w).-   71. The method of any one of paragraphs 44 to 70, further comprising    a preservative, wherein said preservative is a stabilize oxychloro    compound present at a concentration between about 0.001% (w/w) and    about 0.1% (w/w).-   72. The method of any one of paragraphs 44 to 71, further comprising    a buffer, wherein said buffer is boric acid present at a    concentration of about 0.6% (w/w).-   73. The method of any one of paragraphs 44 to 72, further comprising    a pH adjustment agent, wherein said pH adjustment agent is NaOH.-   74. The method of any one of paragraphs 44 to 72, said low salt    ophthalmic pharmaceutical composition having pH of about 7.3.-   75. The method of paragraph 74, wherein said low salt ophthalmic    pharmaceutical composition comprises: castor oil at a concentration    between about 0.01% (w/w) and about 10% (w/w); polysorbate 80 at a    concentration between about 0.01% (w/w) and about 1.0% (w/w);    acrylate/C10-C30 acrylate crosspolymer at a concentration between    about 0.01% (w/w) and about 1.0% (w/w), wherein said    acrylate/C10-C30 acrylate crosspolymer has a standard emulsion    viscosity between 1,700 and 4,500 cPs; carboxymethylcellulose sodium    at a concentration between about 0.01% (w/w) and about 1.0% (w/w);    glycerin at a concentration between about 0.01% (w/w) and about 5.0%    (w/w); a stabilized oxychloro complex preservative at a    concentration between about 0.001% (w/w) and about 0.1% (w/w); boric    acid at a concentration of about 0.6% (w/w); erythritol at a    concentration of about 0.25% (w/w); levocarnitine at a concentration    of about 0.25% (w/w); NaOH; and water.-   76. The method of paragraph 75, wherein said low salt ophthalmic    pharmaceutical composition comprises: castor oil at a concentration    of about 0.25% (w/w); polysorbate 80 at a concentration of about    0.5% (w/w); acrylate/C10-C30 acrylate crosspolymer at a    concentration of about 0.1% (w/w), wherein said acrylate/C10-C30    acrylate crosspolymer has a standard emulsion viscosity between    1,700 and 4,500 cPs; carboxymethylcellulose sodium at a    concentration of about 0.5% (w/w); glycerin at a concentration of    about 1.0% (w/w); a stabilized oxychloro complex preservative at a    concentration of about 0.01% (w/w); boric acid at a concentration of    about 0.6% (w/w); erythritol at a concentration of about 0.25%    (w/w); levocarnitine at a concentration of about 0.25% (w/w); NaOH;    and water.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts the dependence of viscosity (cPs) on salt concentrationfor a low salt ophthalmic pharmaceutical composition disclosed herein.See Example 1. FIG. 1B depicts a histogram of percent change inviscosity upon dilution with water and salt for the sample and controldescribed in Example 1. Legend (left to right): undiluted (open);diluted 20:1 with water (horizontal stripes); diluted 20:1 with 9% NaCl(diagonal stripes).

FIGS. 2A-2B depict overlaid real-time integrated optical detector scansin a time-controlled centrifuge of undiluted sample (FIG. 2A) andcontrol (FIG. 2B) as described in Example 2. Legend: X-axis: position(mm) along the centrifugal chamber; Y-axis: light transmissions (% T).

FIGS. 3A-3B depict overlaid real-time integrated optical detector scansin a time-controlled centrifuge of sample (FIG. 3A) and control (FIG.3B) diluted 1:20 with water, as described in Example 2. Legend: as inFIGS. 2A-2B.

FIGS. 4A-4B depict overlaid real-time integrated optical detector scansin a time-controlled centrifuge of sample (FIG. 4A) and control (FIG.4B) diluted 1:20 with 9% NaCl solution, as described in Example 2.Legend: as in FIGS. 2A-2B.

DETAILED DESCRIPTION OF THE INVENTION I. DEFINITIONS

The term “about” in the context of a numerical value refers, absentexpress indication otherwise, to the nominal amount ±10% thereof.

The terms “clear,” “clarity” and the like in the context of ophthalmicpharmaceutical compositions refer to absorbance and/or light scattering(e.g., opacity, pearlescence, and the like) which are sufficiently lowsuch that the ophthalmic pharmaceutical composition appearssubstantially free of haziness, mistiness or cloudiness to the nakedhuman eye. A clear ophthalmic pharmaceutical composition does notinclude emulsions that visibly separate into a hydrophobic portion and ahydrophilic portion.

The terms “compatible solute,” “osmolytes” and the like in the contextof ophthalmic pharmaceutical compositions refers to substances that aretaken into the cell and act to counterbalance the osmotic pressure foundoutside the cell. Without wishing to be bound by any theory, it isbelieved that compatible solutes have osmoprotective properties whichmay protect the surface cells of the eye from osmotic stress. It isfurther believed that the incorporation of compatible solutes increasesthe clinical usefulness of the composition disclosed herein tocontemplate a broader range of subject suffering from dry eye syndromecompared to previous emulsion systems which target lipid deficiency perse or meibomian gland dysfunction.

The terms “dry eye,” “dry eye syndrome,” “keratitis sicca,”“xerophthalmia,” “keratoconjunctivitis sicca,” and the like refer in thecustomary sense to a condition or spectrum of conditions wherein the eyeis unable to maintain a healthy tear layer (i.e., tear film) sufficientto coat the eye. Dry eye syndrome is more prevalent with age, assubjects typically produce fewer tears with age.

As used herein, the term “effective amount” or “effective dose” refersin the customary sense to an amount which is sufficient to bring about adesired result. Accordingly, a therapeutically effective amount employedin a treatment is a sufficient amount to reduce the extent, undesirableclinical manifestation, of both, of a disease, disorder or condition.

“Formulation,” “composition,” and “preparation” as used herein areequivalent terms referring to a composition of matter suitable forpharmaceutical use (i.e., producing a therapeutic effect as well aspossessing acceptable pharmacokinetic and toxicological properties).

The term “low salt” as used herein in the context of an ophthalmicpharmaceutical composition refers to a salt content which issufficiently low so as to provide a stabilized sub-micron emulsionwithin the ophthalmic pharmaceutical composition. Salt content can bemeasured by a variety of methods known in the art, e.g., measurement ofionic strength. Accordingly, the term “low salt ophthalmicpharmaceutical composition” refers to a pharmaceutical composition foruse in the eye having sufficiently low salt content that a sub-microemulsion which includes a surfactant and a therapeutic lipid is stabletherein.

The term “polymer lubricant” refers to a polymeric agent able coat theocular surface (i.e., demulcent) and provide lubrication to the eye.Exemplary polymer lubricants useful in the composition and methodsdisclosed herein include any of a variety of cellulose derivatives,e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose and the like, polyvinyl pyrrolidone, polyvinyl alcohol, andthe like, and mixtures thereof.

The term “prevent” as used herein refers to a decrease in the occurrenceof dermatological symptoms (e.g., urticarial wheals) in a patient. Theprevention may be complete (i.e., no detectable symptoms) or partial, sothat fewer symptoms are observed than would likely occur absenttreatment.

As used herein, the terms “prevent” and “treat” are not intended to beabsolute terms. Treatment can refer to any delay in onset, e.g.,reduction in the frequency or severity of symptoms, amelioration ofsymptoms, improvement in patient comfort, reduction in symptoms of dryeye, and the like. The effect of treatment can be compared to anindividual or pool of individuals not receiving a given treatment, or tothe same patient before, or after cessation of, treatment.

The terms “salt-sensitive viscosity modulating polymer,” “salt-sensitivepolymer” and the like refer to polymeric agents useful to maintain astable sub-micron emulsion under low salt conditions within a low saltophthalmic pharmaceutical composition disclosed herein, and which inturn destabilize, upon an increase in salt content, the sub-micronemulsion. The term “destabilize” in this context refers to a change inthe sub-micron emulsion such that therapeutic lipid is released from thesub-micron emulsion. Accordingly, the terms “salt-sensitive” and thelike in this context refer to a change in one or more properties of acompound (e.g., conformation, extent of hydration, effective charge dueto ion screening, viscosity and the like) in response to a change insalt concentration. Exemplary salt-sensitive viscosity modulatingpolymers include polymers of acrylic acid which are crosslinked withpolyalkenyl ethers or divinyl glycol. A preferred salt-sensitiveviscosity modulating polymer includes crosslinked copolymers of acrylicacid and C₁₀-C₃₀ alkyl acrylate, commonly referred to as Pemulen™ TR-2(Lubrizol Corporation, Wickliffe, Ohio).

The term “sorbitan ester” in the context of surfactants refers in thecustomary sense to a class of polyethylene glycol (i.e., PEG)derivatives of sorbitan which are further esterified with fatty acids,as known in the art.

The term “standard emulsion viscosity” as used herein refers to theexperimentally determined viscosity of a 0.2% solution of salt-sensitiveviscosity modulating polymer as measured in a standardized procedureaccording to manufacturer's recommendation. See e.g., Lubrizol TestProcedure SA-015, Ed: August 2003, Lubrizol Advanced Materials, Inc.,Cleveland, Ohio.

The term “sub-micron emulsion” refers to an emulsion containingcomponents having an extent in the longest dimension of less than about1 micron. “Emulsion” refers in the customary sense to a mixture of twoor more immiscible liquid components, one component (e.g., a therapeuticlipid described herein or mixture thereof including surfactant) beingdispersed through the other component (e.g., the aqueous component of acomposition described herein).

The term “surfactant” refers in the customary sense to compounds able tolower the surface tension of liquid, the interfacial tension between twoliquids, or the surface tension between a liquid and a solid.

Unless indicated otherwise, the term “tear” as used herein refers in thecustomary sense to the basal tears of the mammalian eye which functionto continuously bathe and nourish the cornea. Other types of tearinclude reflex tears resulting e.g., from irritation of the eye byforeign particles or lacrimator compounds, and psychic tears resulting,e.g., from strong emotional stress, anguish, or physical pain.

The terms “tear film,” “precorneal film” and like refer in the customarysense to the multilayered coating of the normal eye which includes aninnermost mucous layer, a middle aqueous layer, and an outermost lipidlayer. The innermost mucous layer contains proteins, e.g., mucinproduced by the goblet cells of the conjunctiva, and facilitates evenspreading of the overlying middle aqueous layer, e.g., by providing ahydrophilic layer coating the cornea. The middle aqueous layer isproduced by the lacrimal glands and includes water, proteins and salt asknown in the art. The outermost lipid layer contains oils produced bythe meibomian glands and coats the middle aqueous layer, providing ahydrophobic barrier that envelopes tears and prevents outflow, e.g., tothe cheek. Importantly, the outermost lipid layer decreases evaporationof the middle aqueous layer.

The term “therapeutic lipid” refers to a pharmaceutically acceptableamphiphilic or hydrophobic agent which acts to supplement and/or enhancethe naturally occurring oils produced by the meibomian glands which formthe outermost lipid layer of the tear film. In some embodiments, thetherapeutic lipid is a hydrophobic agent. Without wishing to be bound byany theory, it is believed that symptoms of dry eye syndrome can resultfrom insufficient production of naturally occurring oils produced by themeibomian glands. Accordingly, it is further believed that supplementand/or enhancement by a therapeutic lipid described herein is beneficialto the treatment of dry eye syndrome.

The term “therapeutically effective amount” as used herein refers tothat amount of the composition or agent in a composition sufficient toameliorate one or more aspects of the disorder.

Therapeutic efficacy can also be expressed as “-fold” increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

The term “tonicity agent” as used herein refers in the customary senseto a compound which can modulate the effective osmotic pressure within acell. For example, for comfort during administration or instillation,the tonicity of pharmaceutical dosage forms can be adjusted by atonicity agent. Exemplary tonicity agents include dextrose, glycerin,mannitol, KCl, and NaCl. Tonicity agents can provide additional benefit,including e.g., function as a humectant or lubricant.

The term “treatment” as used herein refers to an approach (e.g., aprocedure or regimen) for obtaining beneficial or desired results,including clinical results. “Treating,” “palliating,” or “ameliorating”a disease, disorder or condition means that the extent, undesirableclinical manifestations, or both, of a disease, disorder or conditionare lessened and/or the time course of the progression is slowed (i.e.,lengthened in time), as compared to not treating the disease, disorderor condition. For purposes of the methods disclosed herein, beneficialor desired clinical results include, but are not limited to, alleviationor amelioration of one or more symptoms (e.g., symptoms of dry eyesyndrome), diminishment of extent of disorder, stabilized (i.e., notworsening) state of disorder, delay or slowing of disorder progression,amelioration or palliation of the disorder, and remission (whetherpartial or total), whether detectable or undetectable.

“Treating” and “treatment” as used herein may include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of an active agent. The administeringstep may consist of a single administration or may include a series ofadministrations. The length of the treatment period depends on a varietyof factors, such as the severity of the condition, the age of thepatient, the concentration of active agent, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

Delivering lipids to the human tear film to supplement and enhance thenative lipid layer, often deficient due to dysfunction of meibomianglands and other causes, is a recognized strategy in treating signs andsymptoms of dry eye. This is in theory especially beneficial in lowhumidity or when other internal/external factors increase tear filmevaporation. Excessive loss of water from the tear film causes anincrease in salt content and causes hyperosmotic stress to the cells ofthe ocular surface.

The native lipid layer is very thin and the total volume of lipid is asmall fraction of the total tear film volume. To enhance the structureand function of the lipid layer by topical application of alipid-containing drop requires only a small volume of oil to bedelivered; excess lipid will displace and disrupt the total aqueousvolume, by far the greatest component of tears. It is also necessarythat the lipid be delivered quickly, during the brief contact time of atopical eye drop. Finally, the lipid delivered needs to becomeestablished as part of the native lipid layer, at the air interface.

The challenge of lipid release from an emulsion has been approached byusing substantial amounts of lipid (1-5%) and/or building an emulsionsystem that readily separates. The disadvantage of this approachincludes: the product requires shaking, the clarity of the emulsion isgreatly reduced, the total volume of lipid delivered to the eye ispotentially large and variable and tolerability can be lower than afully aqueous eye drop.

An alternate means of lipid release involves the use of a salt-sensitiveemulsion system in a product intended for topical use that is largelyfree of salt. This system uses a surfactant and viscosity-increasingpolymer to hold the lipid (eg. castor oil) in a stable sub-micronemulsion. When mixed with human tear, the natural salt content (oftenfurther elevated in dry eye) is sufficient to rapidly cause a drop-inproduct viscosity due to action on the polymer structure. This loss ofviscosity allows lipid release to occur to a significantly greaterdegree and much faster.

Efficiency of lipid delivery can be defined as the amount of lipidreleased from the emulsion, as a proportion of total lipid content, overtime under standard test conditions.

Efficiency of lipid delivery in the presence of salt is supported, forexample, using simple laboratory methods. Specifically, when dilutedwith water, this system shows a loss of viscosity proportional to watervolume added. When exposed to salt (NaCl) by mixing 1:1 with even a weaksaline solution (30 mOsm) a loss of viscosity of over 60% occurs vs. 50%when mixed with water. Higher saline strength (up to about 600 mOsm)caused significantly greater loss of viscosity, confirming action ofsalt on polymer structure.

The release of lipid was demonstrated using a controlled centrifuge withreal-time integrated optical detector (Lumisizer). During 2 minutes of4000 RPM stress, uniformity of the emulsion was confirmed by equivalentoptical transmission from bottom to top of the centrifuge sample holderfor both full strength and water-diluted product. However, diluting theproduct with saline (volume and concentration replicating on-eye use)showed a clear and remarkable change in product uniformity consistentwith lipid release and migration to the top of the sample holder,consistent with “floating” to the air interface. Surprisingly andbeneficially, this may occur without coalescence (no increase in averagelipid droplet size) allowing the lipid to mix into the native layer moreeffectively. Average particle (lipid droplet size) was unchanged whensaline was added (Horiba).

Clinical results have confirmed that the new lipid emulsion system workseffectively in prolonging TBUT (tear break-up time) yet demonstratestolerability and comfort improvements vs. an emulsion more optimized fordrug delivery.

The benefits of using a salt-sensitive emulsion system as shown in theTables, that is largely free of salts, include but are not limited to:

-   -   1) No need to shake the product—excellent in bottle stability        and uniformity;    -   2) Efficient delivery of lipid on eye due to the salt-induced        decrease in viscosity and destabilization of emulsion structure        enabling more efficient lipid release;    -   3) Improved tolerability by lowering total lipid content;    -   4) Effective stabilization and supplementation of the native        lipid layer; and    -   5) Possibly greater delivery of beneficial lipid in patients        with higher tear salt content, a so-called “smart” vehicle.

The incorporation of osmoprotectants (1-carnitine and erythritol) andhumectants/lubricants (glycerin and carboxymethylcellulose increases theclinical usefulness of this product to a broader range of dry eyepatients than other emulsion systems targeting lipid deficiency ormeibomian gland dysfunction.

II. DESIGN RATIONALE

The salt-sensitive viscosity modulating polymers contemplated in thepractice of the compositions and methods disclosed herein undergo asalt-sensitive change in physical properties (e.g., change in viscosity)upon a change in salt concentration in the milieu of a sub-micronemulsion containing the polymers. Specifically, upon an increase in saltconcentration, the sub-micron emulsions undergo a decrease in viscosity.Without wishing to be bound by any theory, it is believed that such adecrease in viscosity is associated with a destabilization of thesub-micron emulsion leading to separation of the lipid phase (e.g.,therapeutic lipid) from associated surfactant, which therapeutic lipidthen becomes available to exert a therapeutic benefit in thesupplementation and enhancement of the outer lipid layer of the tearfilm.

Traditionally, ionic or non-ionic surfactants stabilize oil-in-wateremulsions by the formation of lamellar liquid crystalline layers at theemulsion interface to afford micelles, as known in the art. However, asfurther known in the art, such traditional methods of emulsificationrequire relatively high levels (e.g., 3-7%) of surfactant. Withoutwishing to be bound by any theory, it is believed that thesalt-sensitive viscosity modulating polymers contemplated hereinincrease the stability of oil-in-water emulsions under low saltconditions by thickening and adding structure to the water phase,resulting in an aqueous gel around each oil droplet. Thus, incorporationof salt-sensitive viscosity modulating polymers reduces the requirementfor relatively high levels of surfactant in order to achieve stableemulsification. It is further believed that the hydrophobic portions ofthe salt-sensitive viscosity modulating polymers associate with the oildroplet. Thus, when two emulsified oil droplets approach each other, aphysical repulsive force is generated by the presence of the adsorbedgel layers. Accordingly, the oil droplets do not associate with eachother and remain in a stable sub-micron emulsion. Moreover, bydecreasing the total therapeutic lipid content of the composition, it isbelieved that the compositions disclosed herein provide improvedtolerability in the clinic.

As known in the art, tears (i.e., basal tears) have about the sameosmolality as the internal fluids of the body, equivalent to about 0.9%NaCl (i.e., about 150 mM). Moreover, without wishing to be bound by anytheory, it is believed that in dry eye syndrome, the middle aqueouslayer of the tear film can undergo evaporation leading to increasedlocal salt concentration at the eye. Thus, it has been found thatapplication of a composition disclosed herein to the eye can result indestabilization of the sub-micron emulsion of the composition due to theincreased salt content at the eye, thereby providing therapeutic lipidbeneficial at the surface of the eye. Moreover, without wishing to bebound by any theory, it is believed that higher salt content of thenascent tear film and underlying corneal surface found in dry eyesyndrome can result in greater delivery of therapeutic lipid, due tomore effective destabilization of the sub-micron emulsion and release oftherapeutic lipid.

Moreover, it has been surprisingly found that a further benefit of thecompositions disclosed herein is a lack of coalescence of thetherapeutic lipid upon instillation in the eye, resulting in no increasein lipid droplet size. Accordingly, the lipid can mix more effectivelyinto the native tear film.

III. COMPOSITIONS

In a first aspect, there is provided a low salt ophthalmicpharmaceutical composition which includes a sub-micron emulsion, apolymer lubricant, and a salt-sensitive viscosity modulating polymer.The sub-micron emulsion includes a surfactant and a therapeutic lipid.

In one embodiment, the low salt ophthalmic pharmaceutical composition isclear. In one embodiment, the composition has approximately the sameclarity as pure water (e.g.

upon inspection with the naked human eye). Thus, in some embodiments,the composition scatters sufficiently low levels of visible light thatthe composition appears clear to the eye. In one embodiment, thecomposition is effectively clear. The term “effectively clear” refers toa small amount of absorbance and/or light scattering which nonethelessallows light to transit the composition without appreciable blurringand/or distortion. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 20% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 25% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 30% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 35% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 40% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 45% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least about 50% Tof visible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 55% T ofvisible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 60% T ofvisible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 65% T ofvisible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 70% T ofvisible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 75% T ofvisible light. In some embodiments, the clear low salt ophthalmicpharmaceutical composition allows transmission of at least 80% T ofvisible light. Absent an indication otherwise, “% T” refers topercentage transmission of light using a path length of 1 cm.

Further to any embodiment disclosed herein, in one embodiment thetherapeutic lipid is a fatty acid glyceride. In one embodiment, thefatty acid glyceride is a castor oil, olive oil, peanut oil, corn oil,or sunflower oil.

In one embodiment, the therapeutic lipid is castor oil. In oneembodiments, the castor oil is present at a concentration between about0.01% (w/w) and about 10% (w/w). In one embodiment, the castor oil ispresent at a concentration of about 0.25% (w/w).

In one embodiment, the composition includes a plurality of therapeuticlipids. For example, in one embodiment the therapeutic lipid is a firsttherapeutic lipid, and the low salt ophthalmic pharmaceuticalcomposition further includes a second therapeutic lipid. In oneembodiment, the composition further includes a third therapeutic lipid.In one embodiment, the composition further includes a fourth therapeuticlipid, in one embodiment, the composition further includes a fifththerapeutic lipid. Further to each embodiment contemplating a pluralityof therapeutic lipids, the first, second, third, fourth and fifththerapeutic lipids are each different and if present are castor oil,olive oil, peanut oil, corn oil, or sunflower oil.

Further to any embodiment including a plurality of therapeutic lipids,in one embodiment the plurality of therapeutic lipids are present at atotal concentration between about 0.01% (w/w) and about 10% (w/w). Inone embodiment, the plurality of therapeutics lipids are present at aconcentration of about 0.25% (w/w).

In one embodiment, the surfactant within the low salt ophthalmicpharmaceutical composition is a sorbitan ester. Exemplary surfactantscontemplated for use in the compositions and methods disclosed hereininclude polysorbate 20 (i.e., primarily polyoxyethylene [20] sorbitanmonolaurate), polysorbate 40 (i.e., primarily polyoxyethylene [20]sorbitan monopalmitate), polysorbate 60 (i.e., primarily polyoxyethylene[20] sorbitan monostearate), or polysorbate 80 (i.e., polyoxyethylene[20] sorbitan monooleate).

In one embodiment, the surfactant is polysorbate 80. In one embodiment,polysorbate 80 is present at a concentration between about 0.01% (w/w)and about 1.0% (w/w). In one embodiment, polysorbate 80 is present at aconcentration of about 0.5% (w/w).

In one embodiment, the salt-sensitive viscosity modulating polymer ofthe low salt ophthalmic pharmaceutical composition is anacrylate/C₁₀-C₃₀ acrylate crosspolymer. In one embodiment, thesalt-sensitive viscosity modulating polymer has a standard emulsionviscosity between 1,700 and 4,500 cPs. A useful commercially availableacrylate/C₁₀-C₃₀ acrylate crosspolymer is known as PemulenTM TR-2(Lubrizol Corporation, Wickliffe, Ohio).

In one embodiment, the salt-sensitive viscosity modulating polymer ofthe low salt ophthalmic pharmaceutical composition is present at aconcentration between about 0.01% (w/w) and about 1.0% (w/w). In oneembodiment, the salt-sensitive viscosity modulating polymer is presentat a concentration of about 0.1% (w/w).

Further to any embodiment described above, in one embodiment of the lowsalt ophthalmic pharmaceutical composition is a demulcent.

Further to any embodiment described above, in one embodiment the polymerlubricant is a carboxymethylcellulose lubricant. As customarily used inthe art, the terms “carboxymethylcellulose,” “cellulose gum,” “CMC” andthe like refer to cellulose derivatives having carboxymethyl (i.e.,—CH₂—COOH) groups substituted at some of the pendant hydroxyl moietiesof the polymerized D-glucose units forming the linear chain of thecellulose. Cellulose chain length and the degree of carboxymethylationcan be optimized to afford specific properties, including viscositymodulation (i.e., thickening) and stabilization of emulsions.Accordingly, the term “carboxymethylcellulose lubricant” refers to acomposition including one or more carboxymethylcelluloses havingspecific chain lengths and degrees of carboxymethylation.

In one embodiment, the polymer lubricant is carboxymethylcellulosesodium, preferably carboxymethylcellulose sodium (low viscosity, 7LFPH).In one embodiment, the carboxymethylcellulose sodium is present at aconcentration between about 0.01% (w/w) and about 1.0% (w/w). In oneembodiment, the carboxymethylcellulose sodium is present at aconcentration of about 0.5% (w/w).

Further to any embodiment described above, in one embodiment the lowsalt ophthalmic pharmaceutical composition further includes one or morecompatible solutes. Exemplary compatible solutes include polyols andzwitterionic amino acids. In one embodiment, the compatible solute is apolyol. In one embodiment, the compatible solute is a zwitterionic aminoacid. In one embodiment, the compatible solute includes polyols andzwitterionic amino acids. In one embodiment, the compatible soluteincludes a polyol and a zwitterionic amino acid.

In one embodiment, the low salt ophthalmic pharmaceutical compositionincludes erythritol or levocarnitine. In one embodiment, erythritol ispresent at a concentration between about 0.01% (w/w) and about 1.0%(w/w). In one embodiment, levocarnitine is present at a concentrationbetween about 0.01% (w/w) and about 1.0% (w/w). In one embodiment,erythritol is present at a concentration of about 0.25% (w/w). In oneembodiment, levocarnitine is present at a concentration of about 0.25%(w/w). In one embodiment, erythritol is present at a concentration ofabout 0.25% (w/w), and levocarnitine is present at a concentration ofabout 0.25% (w/w).

Further to any embodiment described above, in one embodiment the lowsalt ophthalmic pharmaceutical composition further includes one or moretonicity agents. It is understood that a tonicity agent, e.g., glycerin,can also function as a demulcent. Thus, in one embodiment the tonicityof the low salt ophthalmic pharmaceutical composition is a demulcent.

In one embodiment, the tonicity agents of the low salt ophthalmicpharmaceutical composition is glycerin present at a concentrationbetween about 0.01% (w/w) and about 5.0% (w/w). In one embodiment,glycerin is present at a concentration of about 1.0% (w/w).

Further to any embodiment described above, in one embodiment the lowsalt ophthalmic pharmaceutical composition further includes apreservative. Exemplary preservatives employed in topic ophthalmicpharmaceutical compositions include quaternary ammonium (e.g.,benzalkonium chloride, polyquaternium-1, and the like), mercurials(e.g., thimerosal), alcohols (e.g., chlorobutanol, benzyl alcohol, andthe like), carboxylic acids (e.g., sorbic acid and the like), phenols(methyl or propyl parabens), amidines (e.g., chlorhexidine), and othercompounds (e.g., stabilized oxychloro complex). An exemplary stabilizedoxychloro complex is Purite® (Purite Ltd, Oxon, UK).

In one embodiment, the low salt ophthalmic pharmaceutical compositionincludes a stabilized oxychloro complex. In one embodiment, thestabilized oxychloro complex is present at a concentration between about0.001% (w/w) and about 0.1% (w/w). In one embodiment, the stabilizedoxychloro complex is present at a concentration of about 0.01% (w/w).

Further to any embodiment described above, in one embodiment the lowsalt ophthalmic pharmaceutical composition further includes a buffer.Exemplary buffers useful in the compositions disclosed herein includeinorganic acids (e.g., borate, phosphate, and the like), organic acids(e.g., lower alkyl carboxylic acids), and amines including primary,secondary, tertiary and quaternary amines as known in the art. The term“lower alkyl carboxylic acid” refers to C₁-C₆ alkyl having at least one—COOH substituent.

In one embodiment of the low salt ophthalmic pharmaceutical composition,the buffer is boric acid present at a concentration between about 0.01%(w/w) and about 1.0% (w/w). In one embodiment, boric acid is present ata concentration of about 0.6% (w/w).

Further to any embodiment described above, in one embodiment the lowsalt ophthalmic pharmaceutical composition further includes a pHadjustment agent. Exemplary pH adjustment agents include strong acids(e.g., HCl) and strong bases (e.g., NaOH). In one embodiment, the pHadjustment agent is NaOH. In one embodiment, the pH of the low saltophthalmic pharmaceutical composition is in the range of about pH 7 topH 8. In one embodiment, the pH of the low salt ophthalmicpharmaceutical composition is about pH 7.3.

Further to any embodiment described above, in one embodiment low saltophthalmic pharmaceutical composition includes castor oil at aconcentration between about 0.01% (w/w) and about 10% (w/w); polysorbate80 at a concentration between about 0.01% (w/w) and about 1.0% (w/w);acrylate/C10-C30 acrylate crosspolymer at a concentration between about0.01% (w/w) and about 1.0% (w/w), wherein said acrylate/C10-C30 acrylatecrosspolymer has a standard emulsion viscosity between 1,700 and 4,500cPs; carboxymethylcellulose sodium at a concentration between about0.01% (w/w) and about 1.0% (w/w); glycerin at a concentration betweenabout 0.01% (w/w) and about 5.0% (w/w); a stabilized oxychloro complexpreservative at a concentration between about 0.001% (w/w) and about0.1% (w/w); boric acid at a concentration of about 0.6% (w/w);erythritol at a concentration of about 0.25% (w/w); levocarnitine at aconcentration of about 0.25% (w/w); NaOH; and water. See Table III. Withreference to Tables I and II and III, the term “q.s.” refers in thecustomary sense to a sufficient amount to afford the nominal amount orpH.

TABLE II Range of components of low salt ophthalmic pharmaceuticalcomposition. Range of Approximate Component Amounts Units FunctionPolysorbate 80 0.01 to 1.0 % (w/w) Surfactant Carboxymethyl 0.01 to 1.0% (w/w) Polymer lubricant cellulose sodium Glycerin 0.01 to 5.0 % (w/w)Tonicity agent stabilized oxychloro 0.001 to 0.1  % (w/w) Preservativecomplex Boric acid 0.6  % (w/w) Buffer Acrylate/C₁₀-C₃₀ 0.01 to 1.0 %(w/w) Salt-sensitive viscosity acrylate modulating polymer crosspolymer(Pemulen ™ TR-2) Castor oil 0.01 to 10  % (w/w) Therapeutic lipidErythritol 0.25 % (w/w) Compatible solute Levocarnitine 0.25 % (w/w)Compatible solute NaOH q.s. to pH 7.3 pH QS Adjustment Water forinjection q.s. to 100% % (w/w) QS Adjustment

In one embodiment, the low salt ophthalmic pharmaceutical compositionhas a formulation as set forth in Table III following.

TABLE III Exemplary low salt ophthalmic pharmaceutical composition.Range of Approximate Component Amounts Units Function Polysorbate 80 0.5% (w/w) Surfactant Carboxymethyl 0.5 % (w/w) Polymer lubricant cellulosesodium Glycerin 1.0 % (w/w) Tonicity agent stabilized oxychloro 0.01 %(w/w) Preservative complex Boric acid 0.6 % (w/w) BufferAcrylate/C₁₀-C₃₀ 0.1 % (w/w) Salt-sensitive viscosity acrylatemodulating polymer crosspolymer (Pemulen ™ TR-2) Castor oil 0.25 % (w/w)Therapeutic lipid Erythritol 0.25 % (w/w) Compatible soluteLevocarnitine 0.25 % (w/w) Compatible solute NaOH q.s. to pH 7.3 pH QSAdjustment Water for injection q.s. to 100% % (w/w) QS Adjustment

IV. METHODS OF USE

In another aspect, there is provided a method for treating dry eyesyndrome. The method includes administering to a subject in need oftreatment of dry eye syndrome a therapeutically effective amount of alow salt ophthalmic pharmaceutical composition as disclosed herein,thereby treating dry eye syndrome in the subject. In one embodiment, thelow salt ophthalmic pharmaceutical composition includes a sub-micronemulsion, a polymer lubricant, and a salt-sensitive viscosity modulatingpolymer, as disclosed herein, wherein the sub-micron emulsion includes asurfactant and a therapeutic lipid.

In one embodiment, the therapeutic lipid within the low salt ophthalmicpharmaceutical composition is castor oil at a concentration betweenabout 0.01% (w/w) and about 10% (w/w).

In one embodiment, the surfactant is polysorbate 80 at a concentrationbetween about 0.01% (w/w) and about 1.0% (w/w).

In one embodiment, the salt-sensitive viscosity modulating polymerincludes acrylate/C10-C30 acrylate crosspolymer present at aconcentration between about 0.01% (w/w) and about 1.0% (w/w). In oneembodiment, the salt-sensitive viscosity modulating polymer has astandard emulsion viscosity between 1,700 and 4,500 cPs.

In one embodiment, the polymer lubricant is carboxymethylcellulosesodium present at a concentration between about 0.01% (w/w) and about1.0% (w/w).

In one embodiment, the low salt ophthalmic pharmaceutical compositionfurther includes a compatible solute. In one embodiment, the compatiblesolute is erythritol at a concentration of about 0.25% (w/w) andlevocarnitine at a concentration of about 0.25% (w/w).

In one embodiment, the low salt ophthalmic pharmaceutical compositionfurther includes a tonicity agent. In one embodiment, the tonicity agentis glycerin at a concentration between about 0.01% (w/w) and about 5.0%(w/w).

In one embodiment, the low salt ophthalmic pharmaceutical compositionfurther includes a preservative. In one embodiment, the preservative isa stabilize oxychloro compound present at a concentration between about0.001% (w/w) and about 0.1% (w/w).

In one embodiment, the low salt ophthalmic pharmaceutical compositionfurther includes a buffer. In one embodiment, the buffer is boric acidpresent at a concentration of about 0.6% (w/w).

In one embodiment, the low salt ophthalmic pharmaceutical compositionfurther includes a pH adjustment agent. In one embodiment, the pHadjustment agent is NaOH.

In one embodiment, the low salt ophthalmic pharmaceutical compositionhas a pH of about 7.3.

In one embodiment, the low salt ophthalmic pharmaceutical compositionincludes the components as set forth in Table 1. In one embodiment, thelow salt ophthalmic pharmaceutical composition includes the componentsas set forth in Table II.

V. EXAMPLES Example 1 Effect of Dilution on Viscosity With and WithoutSalt

A low salt ophthalmic pharmaceutical composition was formulated todeliver therapeutic lipid and lubricating polymers to the precornealtear fluid. A salt-sensitive viscosity modulating polymer, as disclosedherein, was used to stabilize the lipid in solution yet allow efficientlipid delivery on the eye when mixed with salts in the tear film uponinstillation. Delivery of therapeutic lipid to the lipid layer of thetear film was modeled by diluting the low salt ophthalmic pharmaceuticalcomposition with a salt solution and measuring the associated change inviscosity and lipid distribution. As control, the results were comparedwith a marketed emulsion eye drop lacking salt-sensitive viscositymodulating polymer. The term “sample” in this section refers to a lowsalt ophthalmic pharmaceutical composition as set forth in Table 2above. The term “control” refers to a marketed emulsion eye drop lackingsalt-sensitive viscosity modulating polymer.

Methods. Viscosity change measurements employed a Brookfield viscometer(25° C., spindle 18, 30 rpm) (Brookfield Engineering laboratories,Middleboro, Mass.), before and after dilution of sample 1:1 with wateror salt solution ranging from 30 to 600 mOsm NaCl.

Viscosity measurements were repeated with concentrated NaCl to confirminitial results.

Results. As depicted in FIG. 1A, the viscosity of the tested sampledecreased monotonically as a function of salt concentration. Whendiluted 1:1 with water, the viscosity of the sample was reduced by about51%. When diluted 1:1 with 30 to 600 mOsm NaCl, the viscosity loss was62.7% to 78.0%.

In contrast, the control composition displayed equivalent reduction inviscosity upon dilution with either water to salt solution.

As shown in FIG. 1B, dilution of the sample of low salt ophthalmicpharmaceutical composition at 20:1 with water or 9% NaCl afforded apercent change reduction in viscosity of about 9% or about 49%,respectively. In contrast, dilution of the control eye drop compositionresulted in a percent change reduction in viscosity of about 8% and 1%,respectively, for dilution 20:1 with water and 9% NaCl.

Summary. The viscosity reduction upon increased salt concentration in asample low salt ophthalmic pharmaceutical composition was greater thanobserved for the control eye drop lacking salt-sensitive viscositymodulating polymer. The greatest viscosity difference for the sample wasobserved between dilution with water and dilution with 37 mOsm NaCl. Incontrast, the viscosity of the control was observed to correlate onlywith dilution and not with salt concentration.

Example 2 Effect of Stability of Water and Salt Concentration

Introduction. The stability and uniformity of the emulsions described inExample 1 was investigated under undiluted and diluted conditions.

Methods. Assessment of stability and uniformity of sample compositionsemployed a time-controlled centrifuge with integrated optical detector(Lumisizer®, L.U.M. GmbH, Berlin, Germany). Samples were undiluted, ordiluted 1:20 with water or concentrated (9%) NaCl resulting in a finalconcentration of 0.45% NaCl simulating the saline concentration of adrop of ophthalmic pharmaceutical composition on the tear film.Concentrated NaCl was used to minimize the dilution effect on lighttransmittance. Scans were taken repetitively for 2-min at 4000 rpm.

Results. As shown in FIG. 2A, an undiluted sample of the low saltophthalmic pharmaceutical composition is stable with time. Lighttransmission (% T) for the sample is approximately 55%. In contrast, asshown in FIG. 2B, the undiluted control eye drop lacking salt-sensitiveviscosity modulating polymer is slightly unstable as indicated by thechange over time at the distal end of the integrated optical detector ofthe time-controlled centrifuge. Moreover, the light transmission in thecontrol is significantly lower, having a value of about 12% (% T) priorto the changes which accompany the destabilization of the control.Without wishing to be bound by any theory, it is believed that changesin % T correlate with release of lipid which migrates to the top (i.e.,distal end) of the centrifuge chamber, consistent with floating of lipidto the air interface of the aqueous layer of the tear film.

As shown in FIGS. 3A-3B, upon dilution 1:20 with water, both the sampleand control show increase in % T due to dilution. Stability in bothexperiments is similar to that observed in the undiluted state.

As shown in FIG. 4A, upon dilution 1:20 with 9% NaCl, the sample issignificantly destabilized with rapid release of oil and transient dropin % T. In contrast, as shown in FIG. 4B, the stability of the controlis similar to that observed with water dilution.

Summary. The low salt ophthalmic pharmaceutical composition sample wasstable and uniform in the undiluted state, as occurs in storage prior touse. This demonstrates the surprising benefit of excellent stability anduniformity in storage, while requiring no shaking of the compositionprior to instillation. In contrast, the control eye drop lackingsalt-sensitive viscosity modulating polymer is slightly unstable instorage. When mixed with salt, the viscosity of the sample droppedsignificantly. In contrast, the control did not demonstrate a dependenceof stability on salt concentration. Without wishing to be bound by anytheory, it is believed that the reduction in viscosity in the sampledestabilizes the structure of the emulsion, resulting in release oflipid. Accordingly, the use of a salt-sensitive viscosity modulatingpolymer within the sample increases delivery of lipids at the oculartarget.

Example 3 Lipid Droplet Particle Size Upon Dilution with Salt

Lipid particle size in solution can be determined by a variety oftechniques known in the art, including e.g., laser diffraction, dynamicimage analysis, static image analysis, and dynamic light scattering. Thechange in lipid droplet size within formulations disclosed herein uponinstillation in the eye was determine in model systems by dilution withsalt solution.

Methods. Average particle size (lipid droplet size) was determined usinga Horiba particle size analysis system (Horiba, Ltd., Fukuoka Japan).The sample composition and salt solutions were as described in Examples1-2.

Results. Upon dilution with salt solution, the average particle size(i.e., lipid droplet size) was unchanged (data not shown).

Summary. The lipid droplet size of tested formulations does not changeupon an increase in salt concentration. Accordingly, the lipid dropletsremain sufficiently small to provide effective incorporation of lipidinto the tear film.

Example 4 Clinical Studies

Tear breakup time (TBUT) is recognized as a useful procedure in thediagnosis of dry eye syndrome and related conditions. As known in theart, compositions and methods which increase TBUT can be beneficial inthe treatment. Thus, clinical studies were conducted which measured TBUTfor a low salt ophthalmic pharmaceutical composition disclosed herein.Moreover, the clinical studies included tolerability and comfortassessments, as known in the art.

Methods. The fluorescein tear breakup time procedure was employed, asknown in the art. Results. The low salt ophthalmic pharmaceuticalcomposition set forth in Table 2 above was observed to prolong TBUT.Moreover, the composition demonstrates clinical tolerability andcomfort. Example 5 Clinical Studies

A Multicenter, Investigator-masked, Randomized, 4-Arm, Parallel-groupStudy to Evaluate the Safety, Efficacy, and Acceptability of a Unit-doseEye Drop Formulation in Subjects With Dry Eye Disease

The objective of the study was to evaluate the safety, efficacy, andacceptability of the formulation of Table 1, but without containingPurite®, referred to as a Next Generation Emulsion Unit-dose or (“NGEUD”) in subjects with signs and symptoms of dry eye disease.

Methodology

This was a multicenter, investigator-masked, randomized,active-controlled, 4-arm, parallel group study designed to compare thesafety, efficacy, and acceptability of NGE UD to commercially availableOPTIVE™ Sensitive Preservative-free Lubricant Eye Drops Unit-dose(“OPTIVE UD”), NGE UD to Next Generation Emulsion Multidose (“NGE MD”)(same formulation as Table 1 but with Purite®), and NGE MD to OPTIVE™Lubricant Eye Drops Multidose (“OPTIVE MD”).

The planned study duration was 30 days for each subject and consisted ofup to 3 scheduled visits (days 1 [baseline], 7, and 30 [exit]). On day1, eligible subjects with signs and symptoms of dry eye disease wereassigned according to a 2:2:1:1 treatment allocation ratio to use NGEUD, OPTIVE UD, NGE MD, or OPTIVE MD, respectively. The studyrandomization was stratified by baseline Ocular Surface Disease Index©(OSDI) score (mild/moderate symptoms=score of 18 to 32; severe symptoms=score of >32 to 65). Approximately 300 subjects were to be enrolled at13 to 14 sites within the USA in order to have 288 completed subjectsassuming a dropout rate of approximately 5%. Subjects were instructed toinstill 1 to 2 drops of their assigned study product in each eye, asneeded, but at least 2 times daily for 30 days.

Number of Subjects (Planned and Enrolled)

Approximately 300 subjects were planned to be enrolled in this study. Atotal of 315 subjects were enrolled.

Diagnosis and Main Criteria for Eligibility

Diagnosis/Subjects with Signs and Symptoms of Dry Eye Disease

Key Inclusion Criteria:

Male or female subjects, at least 18 years of age, with a baseline(day 1) OSDI score of ≥18 and ≤65 (based on a 0 to 100 scale) wereeligible for enrollment. Subjects must have been using topicalophthalmic drops for dry eye at least twice daily, for at least 3 monthsprior to baseline, on average. If there was daily use of RESTASIS®Cyclosporine Ophthalmic Emulsion, it must have been in use for ≥6months. Three consecutive tear break-up time (TBUT) tests ≤10 seconds inat least 1 eye at baseline were required. Using the modified NationalEye Institute (NEI) Grid, all subjects had to have at least a Grade 1staining in at least 1 of the 5 zones of the cornea or in at least 1 ofthe 6 zones of the conjunctiva that is related to dry eye in at least 1eye at baseline.

Key Exclusion Criteria:

Key exclusion criteria included a Schirmer test (with anesthesia) ≤2 mmin either eye at baseline; corneal or conjunctival staining score of 5(modified NEI Grid) at baseline in any of the 5 corneal or 6conjunctival zones of either eye; use of systemic medications that couldhave affected a dry eye condition or vision, unless that medication hadbeen used at the same dose for at least 3 months prior to studyenrollment and the dosage was not expected to change during the courseof the study; history of anterior segment surgery or trauma that couldhave affected corneal sensitivity (eg, cataract surgery, laser-assistedin situ keratomileusis [LASIK], photorefractive keratectomy, or anysurgery involving a limbal or corneal incision) within 12 months priorto baseline; and current use of, and/or use within 2 weeks prior tobaseline, and/or likely use during the study period of any topicalophthalmic medications (e.g., topical ophthalmic steroids, glaucomadrops, any topical cyclosporine product other than Restasis®. Subjectswho discontinued use of daily Restasis® less than 3 months prior tobaseline were excluded from the study.

Duration of Treatment: The total duration of exposure to the studyproduct (drops) for each subject was 30 days. The visit scheduleconsisted of a baseline visit (day 1) and 2 follow-up visits on days 7(±3 days) and 30/early exit (±7 days).

Efficacy and Safety Measurements Efficacy: Primary—OSDI QuestionnaireScore

Secondary—TBUT (with fluorescein), corneal staining (modified NEI Grid,with fluorescein), conjunctival staining (modified NEI Grid, withlissamine green), and Schirmer test (with anesthesia)

Other—Acceptability Questionnaire and Study Product Usage QuestionnaireSafety:

The safety measures were adverse events, biomicroscopy, and distancevisual acuity.

Statistical Methods:

The intent-to-treat (ITT) population consisted of all randomizedsubjects and was used for analyses of efficacy data based on thetreatment randomized. The safety population consisted of all treatedsubjects and was used for analyses of all safety data based on theactual treatment received. The per-protocol (PP) population consisted ofrandomized subjects who had no major protocol violations, as determinedprior to database lock.

The primary efficacy variable was the change from baseline in OSDI scoreat day 30 in the ITT population. The primary efficacy analysis wasperformed on the change from baseline in OSDI score at day 30 via a2-way analysis of variance (ANOVA) model with treatment and baselineOSDI stratification as the main effects.

Last observation carried forward (LOCF) was used to impute missing data.Noninferiority was tested using a 2-sided confidence interval (CI). Thetreatment difference and 95% CI in change from baseline in OSDI score atday 30 between NGE UD and OPTIVE UD (NGE UD minus OPTIVE UD) werecalculated based on the ANOVA model. Non-inferiority was established ifthe upper limit of the 95% CI was less than the prespecified margin of7.3.

The Secondary efficacy measures included TBUT, corneal staining,conjunctival staining, and Schirmer test. The raw values of thesemeasures were summarized for the ITT population, with missing dataimputation using LOCF at each scheduled follow-up visit. The treatmentdifference and 95% CI for between-treatment comparisons were calculated.The treatment differences and 95% CIs in change from baseline in OSDIscore at day 30 between NGE UD and NGE MD, NGE MD and OPTIVE MD werealso analyzed as secondary efficacy variables.

Acceptability was measured using the Acceptability Questionnaire, andproduct usage was measured using the Study Product Usage Questionnaire.Comparisons across groups were performed using ANOVA model withtreatment and baseline OSDI stratification as the main effects.

The safety variables included adverse events, biomicroscopy, anddistance visual acuity. Since both eyes were treated, both eyes wereincluded in the safety analyses. The Medical Dictionary for RegulatoryActivities (MedDRA) nomenclature was used to code adverse events. Thenumber and percent of subjects with clinically significant biomicroscopyfindings at one or more visits in either eye were tabulated. The overallfrequency distribution was analyzed using Pearson's chi-square test. Fora clinically significant biomicroscopic finding (more than 1 severitygrade increase [worsening] from baseline) with an incidence rate of ≥5%in any treatment group, the mean severity grade and the frequencydistribution of severity scores were summarized at each scheduled visit.

Data from the eye with the worst severity at the scheduled visit wastabulated. For distance visual acuity data, the total numbers of lettersread correctly were summarized based on the eye with worse change frombaseline at each scheduled visit. The frequency distribution wasanalyzed using Pearson's chi-square test.

A total of 315 subjects were enrolled in the study and included in theITT population; 105 subjects in the NGE UD group, 103 subjects in theOPTIVE UD group, 51 subjects in the NGE MD group, and 56 subjects in theOPTIVE MD group. Overall, 310 (98.4%) subjects in the ITT populationcompleted the study. Of the subjects included in the per protocolpopulation, 99.3% (303/305) completed the study whereas 98.4% (310/315)of the subjects in the safety population completed the study. A total of384 subjects were screened of which 69 subjects were screen failures.

In the ITT population, the mean age of all subjects was 54.8 years(standard deviation 14.33) with 83.2% (262/315) of subjects in the >40years age group. In addition, 81.0% (255/315) of all subjects werefemale and 84.4% (266/315) were Caucasian.

Efficacy:

-   The primary efficacy endpoint was met. At day 30, no statistically    significant difference was observed between the NGE UD and the    OPTIVE UD groups in the mean change from baseline in OSDI score (95%    confidence interval [−5.42, 2.51]), in the ITT population. The NGE    UD formulation was noninferior to the OPTIVE UD formulation in    reducing the severity of symptoms of dryness as measured by the    change from baseline in OSDI score.-   Similar to the ITT population, there was no statistically    significant difference between the NGE UD and OPTIVE UD groups of    the PP population in the mean change from baseline in OSDI score at    day 30. The 95% confidence interval at the day 30 visit was (−5.72,    2.37); with an upper limit that is lower than the clinically    relevant margin of 7.3.-   In all 4 treatment groups, there was a statistically significant    difference (p<0.001) in the mean change from baseline in OSDI score    at the day 7 and day 30 visits for both the ITT and the PP    population.-   The NGE UD group was noninferior to the NGE MD group in the mean    change from baseline in OSDI score at day 30.-   The NGE UD group was noninferior to the OPTIVE UD and NGE MD groups    in the secondary efficacy measures of TBUT, corneal staining,    conjunctival staining, and Schirmer test.-   Overall, there were no statistically significant differences between    the NGE UD and OPTIVE UD groups, NGE UD and NGE MD groups, or NGE MD    and OPTIVE MD groups, in the mean values for each question of the    acceptability questionnaire at the day 7 and day 30 visits (except    for question 5 in the NGE MD versus OPTIVE MD comparison at day 7    and NGE UD versus NGE MD comparison at day 30), and in the mean    number of times per day that the study product was used during the    week prior to the day 7 and day 30 visits.

Safety:

-   At least 1 treatment-emergent adverse event (TEAE) of any causality    was reported in 11.4%, 15.5%, 13.7%, and 10.7% of subjects in the    NGE UD, OPTIVE UD, NGE MD and OPTIVE MD groups, respectively.-   No deaths were reported in the study. Two serious adverse events    were reported (bile duct stone [NGE UD group] and ankle fracture    [OPTIVE MD group]), none of which were treatment related in the    opinion of the investigator.-   Overall 3 subjects discontinued from the study due to adverse    events, 1 subject each in the NGE UD, NGE MD and OPTIVE MD groups.-   Treatment-related TEAE were reported in 4.8%, 8.7%, 7.8%, and 5.4%    of subjects in the NGE UD, OPTIVE UD, NGE MD, and OPTIVE MD groups,    respectively. The most common treatment-related adverse events    (preferred terms) across treatment groups were instillation site    pain and vision blurred; NGE UD (3.8%, 2.9%), OPTIVE UD (3.9%,    2.9%), NGE MD (3.9%, 0.0%), and OPTIVE MD (3.6%, 1.8%).-   In the majority of the subjects, no change was observed in the    distance visual acuity at day 30 for all 4 treatment groups.

CONCLUSIONS

Efficacy: The results of this study demonstrate that the NGE UDformulation is non-inferior to the OPTIVE UD formulation in reducing theseverity of symptoms of dryness in subjects with mild to severe dry eye.

Safety: NGE UD appeared to be well tolerated during the study. The mostcommonly reported treatment-related adverse events were instillationsite pain and vision blurred. Throughout the study, there were notreatment-related serious adverse events. The safety profile wasconsistent with OPTIVE UD, OPTIVE MD, and NGE MD. This is supportive ofthe safety of the NGE UD formulation in clinical use, and confirms thesafety of the NGE MD formulation.

What is claimed is:
 1. A low salt ophthalmic pharmaceutical compositioncomprising a sub-micron emulsion, a polymer lubricant, and asalt-sensitive viscosity modulating polymer, wherein said sub-micronemulsion comprises a surfactant and castor oil.
 2. The low saltophthalmic pharmaceutical composition according to claim 1, wherein saidcastor oil present at a concentration of about 0.25% (w/w).
 3. The lowsalt ophthalmic pharmaceutical composition according to claim 1, whereinsaid surfactant is a sorbitan ester, wherein said sorbitan ester ispolysorbate 80 present at a concentration of about 0.5% (w/w).
 4. Thelow salt ophthalmic pharmaceutical composition according to claim 1,wherein said salt-sensitive viscosity modulating polymer is anacrylate/Cio-C30 acrylate crosspolymer having a standard emulsionviscosity between 1,700 and 4,500 cPs.
 5. The low salt ophthalmicpharmaceutical composition according to claim 1, wherein said polymerlubricant is carboxymethylcellulose sodium present at a concentration ofabout 0.5% (w/w).
 6. The low salt ophthalmic pharmaceutical compositionaccording to claim 1, further comprising a compatible solute.
 7. The lowsalt ophthalmic pharmaceutical composition according to claim 6, whereinsaid compatible solute is erythritol or levocarnitine.
 8. The low saltophthalmic pharmaceutical composition according to claim 7 comprisingerythritol at a concentration of about 0.25% (w/w) and levocarnitine ata concentration of about 0.25% (w/w).
 9. The low salt ophthalmicpharmaceutical composition according to claim 1, further comprising atonicity agent, wherein said tonicity agent is glycerin present at aconcentration of about 1.0% (w/w).
 10. The low salt ophthalmicpharmaceutical composition according to claim 1, further comprising apreservative.
 11. The low salt ophthalmic pharmaceutical compositionaccording to claim 10, wherein said preservative is a stabilizedoxychloro complex present at a concentration of about 0.01% (w/w). 12.The low salt ophthalmic pharmaceutical composition according to claim 11further comprising a buffer.
 13. The low salt ophthalmic pharmaceuticalcomposition according to claim 12, wherein said buffer is boric acidpresent at a concentration of about 0.6% (w/w).
 14. The low saltophthalmic pharmaceutical composition according to claim 13 furthercomprising a pH adjustment agent.
 15. The low salt ophthalmicpharmaceutical composition according to claim 14, wherein said pHadjustment agent is NaOH.
 16. The low salt ophthalmic pharmaceuticalcomposition according to claim 14 having pH of about 7.3.
 17. A low saltophthalmic pharmaceutical composition comprising: castor oil at aconcentration of about 0.25% (w/w); polysorbate 80 at a concentration ofabout 0.5% (w/w); acrylate/Cio-C30 acrylate crosspolymer at aconcentration of about 0.1% (w/w), wherein said acrylate/Cio-C30acrylate crosspolymer has a standard emulsion viscosity between 1,700and 4,500 cPs; carboxymethylcellulose sodium at a concentration of about0.5% (w/w); glycerin at a concentration of about 1.0% (w/w); astabilized oxychloro complex preservative at a concentration of about0.01% (w/w); boric acid at a concentration of about 0.6% (w/w);erythritol at a concentration of about 0.25% (w/w); levocarnitine at aconcentration of about 0.25% (w/w); NaOH; and water.
 18. A method fortreating dry eye syndrome comprising: administering to a subject in needof treatment of dry eye syndrome a low salt ophthalmic pharmaceuticalcomposition according to claim 17; thereby treating said dry eyesyndrome.
 19. The method of claim 18 wherein the ophthalmic compositionis applied at least once a day to treat dry eye.
 20. The method of claim19 wherein the ophthalmic composition reduces pain and inflammationassociated with dry eye.